MKKS

Summary

MKKS (MKKS centrosomal shuttling protein, HGNC:7108) is a protein-coding gene on chromosome 20p12.2, encoding Molecular chaperone MKKS (Q9NPJ1). Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis.

This gene encodes a protein which shares sequence similarity with other members of the type II chaperonin family. The encoded protein is a centrosome-shuttling protein and plays an important role in cytokinesis. This protein also interacts with other type II chaperonin members to form a complex known as the BBSome, which involves ciliary membrane biogenesis. This protein is encoded by a downstream open reading frame (dORF). Several upstream open reading frames (uORFs) have been identified, which repress the translation of the dORF, and two of which can encode small mitochondrial membrane proteins. Mutations in this gene have been observed in patients with Bardet-Biedl syndrome type 6, also known as McKusick-Kaufman syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8195 — RefSeq curated summary.

At a glance

• Gene–disease (curated): MKKS-related ciliopathy (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 668 total — 53 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 134
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_170784

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7108
Approved symbol	MKKS
Name	MKKS centrosomal shuttling protein
Location	20p12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000125863
Ensembl biotype	protein_coding
OMIM	604896
Entrez	8195

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000347364, ENST00000399054, ENST00000651692, ENST00000652676

RefSeq mRNA: 2 — MANE Select: NM_170784 NM_018848, NM_170784

CCDS: CCDS13111

Canonical transcript exons

ENST00000347364 — 6 exons

Exon	Start	End
ENSE00000859107	10407616	10407726
ENSE00000859109	10408628	10408803
ENSE00001206258	10434108	10434222
ENSE00001206284	10412530	10413931
ENSE00001226222	10420528	10420758
ENSE00002622723	10401009	10405687

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 95.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.6382 / max 273.2724, expressed in 1822 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186424	47.5705	1821
186423	0.8371	526
208993	0.2306	106

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	95.17	gold quality
endothelial cell	CL:0000115	95.05	gold quality
prefrontal cortex	UBERON:0000451	92.85	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.72	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.69	gold quality
right frontal lobe	UBERON:0002810	92.48	gold quality
anterior cingulate cortex	UBERON:0009835	92.18	gold quality
frontal cortex	UBERON:0001870	92.14	gold quality
cingulate cortex	UBERON:0003027	92.09	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.03	gold quality
neocortex	UBERON:0001950	92.00	gold quality
islet of Langerhans	UBERON:0000006	91.98	gold quality
nucleus accumbens	UBERON:0001882	91.89	gold quality
mucosa of transverse colon	UBERON:0004991	91.84	gold quality
caudate nucleus	UBERON:0001873	91.66	gold quality
cerebral cortex	UBERON:0000956	91.49	gold quality
putamen	UBERON:0001874	91.47	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.34	gold quality
ventricular zone	UBERON:0003053	91.27	gold quality
telencephalon	UBERON:0001893	91.23	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.22	gold quality
cerebellar cortex	UBERON:0002129	91.12	gold quality
cerebellar hemisphere	UBERON:0002245	91.11	gold quality
substantia nigra pars compacta	UBERON:0001965	91.00	gold quality
right atrium auricular region	UBERON:0006631	90.98	gold quality
adult mammalian kidney	UBERON:0000082	90.94	gold quality
choroid plexus epithelium	UBERON:0003911	90.87	gold quality
forebrain	UBERON:0001890	90.83	gold quality
primary visual cortex	UBERON:0002436	90.82	gold quality
cerebellum	UBERON:0002037	90.78	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting MKKS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-875-3P	99.63	69.47	2548

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• Unaffected individuals in 2 pedigrees had 2 but not all 3 mutations that affecteds had which suggests that Bardet-Biedle syndrome might not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. (PMID:11567139)
• The presence of three mutant alleles in the BBS family correlates with a more severe Bardet-Biedl phenotype. (PMID:12837689)
• MKKS/BBS6 is a novel centrosomal component required for cytokinesis (PMID:15731008)
• These results indicate that the MKKS mutants have an abnormal conformation and that chaperone-dependent degradation mediated by CHIP is a key feature of McKusick-Kaufman syndrome/Bardet-Biedl syndrome diseases. (PMID:18094050)
• results suggest that genetic variation in the MKKS gene may play a role in the development of obesity and the metabolic syndrome. (PMID:18813213)
• genetic variations at MKKS gene influence the risk of metabolic syndrome (PMID:19247371)
• Using sequence analysis, the role of BBS6, 10 and 12 was assessed in a Bardet-Biedl syndrome patient population comprising 93 cases from 74 families. (PMID:20472660)
• Novel mutation (c.1272+1G>A) in BBS6 found in Tunisian families with Bardet-Biedl syndrome. (PMID:23432027)
• Three uORFs (uMKKS0, uMKKS1 and uMKKS2) are reported, and they can repress the translation of the downstream MKKS ORF. uMKKS1 and uMKKS2 are highly conserved in mammals and they encode two different mitochondrial membrane proteins respectively. (PMID:23671934)
• Findings indicate that Bbs proteins play a central role in the regulation of the actin cytoskeleton and control the cilia length through alteration of RhoA levels. (PMID:23716571)
• we report here, for the first time, in Indian population, a novel, different profile of mutations in BBS genes (BBS3, BBS9, BBS10 and BBS2) compared to worldwide (BBS1 and 10) reports. (PMID:24400638)
• We identified a novel H395R substitution in MKKS/BBS6 that results in a unique phenotype of only retinitis pigmentosa and polydactyly. (PMID:26900326)
• found compound heterozygous variants (c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants (PMID:28624958)
• Two novel mutations and three previously reported variants, identified in the present study, further extend the body of evidence implicating BBS6, BBS7, BBS8, and BBS10 in causing Bardet-Biedl Syndrome. (PMID:28761321)
• Novel sequence variants in the MKKS gene cause Bardet-Biedl syndrome in two consanguineous families with intra- and inter-familial variable phenotypes. (PMID:29232001)
• Novel mutation in MKKS/BBS6 linked with arRP and polydactyly in a family of North Indian origin. (PMID:31989739)
• Apparent but unconfirmed digenism in an Iranian consanguineous family with syndromic Retinal Disease. (PMID:33741323)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mkks	ENSDARG00000016139
mus_musculus	Mkks	ENSMUSG00000027274
rattus_norvegicus	Mkks	ENSRNOG00000006705

Paralogs (13): PIKFYVE (ENSG00000115020), CCT4 (ENSG00000115484), TCP1 (ENSG00000120438), CCT6B (ENSG00000132141), CCT7 (ENSG00000135624), HSPD1 (ENSG00000144381), CCT6A (ENSG00000146731), CCT5 (ENSG00000150753), CCT8 (ENSG00000156261), CCT3 (ENSG00000163468), CCT2 (ENSG00000166226), BBS12 (ENSG00000181004), CCT8L2 (ENSG00000198445)

Protein

Protein identifiers

Molecular chaperone MKKS — Q9NPJ1 (reviewed: Q9NPJ1)

Alternative names: Bardet-Biedl syndrome 6 protein, McKusick-Kaufman/Bardet-Biedl syndromes putative chaperonin

All UniProt accessions (1): Q9NPJ1

UniProt curated annotations — full annotation on UniProt →

Function. Probable molecular chaperone that assists the folding of proteins upon ATP hydrolysis. Plays a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia. May play a role in protein processing in limb, cardiac and reproductive system development. May play a role in cytokinesis.

Subunit / interactions. Component of a complex composed at least of MKKS, BBS10, BBS12, TCP1, CCT2, CCT3, CCT4, CCT5 and CCT8. Interacts with STUB1. Interacts with BBS2 (via coiled coil domain). Interacts with CCDC28B. Interacts with BBS12. Interacts with SMARCC1, a component of the SWI/SNF complexes; the interaction takes place predominantly in the cytoplasm and may modulate SMARCC1 location. Interacts with DLEC1.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Cytosol. Nucleus.

Tissue specificity. Widely expressed in adult and fetal tissues.

Disease relevance. McKusick-Kaufman syndrome (MKKS) [MIM:236700] Autosomal recessive developmental disorder. It is characterized by hydrometrocolpos, postaxial polydactyly and congenital heart defects. The disease is caused by variants affecting the gene represented in this entry. Bardet-Biedl syndrome 6 (BBS6) [MIM:605231] A syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and intellectual disability. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The substrate-binding apical domain region is sufficient for centrosomal association.

Similarity. Belongs to the TCP-1 chaperonin family.

RefSeq proteins (2): NP_061336, NP_740754* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002423	Cpn60/GroEL/TCP-1	Family
IPR027409	GroEL-like_apical_dom_sf	Homologous_superfamily
IPR027410	TCP-1-like_intermed_sf	Homologous_superfamily
IPR027413	GROEL-like_equatorial_sf	Homologous_superfamily
IPR028790	MKKS	Family

Pfam: PF00118

UniProt features (34 total): sequence variant 30, chain 1, region of interest 1, binding site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPJ1-F1	89.05	0.65

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 192–199

Mutagenesis-validated functional residues (1):

Position	Phenotype
454	no effect on import to the nucleus.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5620922	BBSome-mediated cargo-targeting to cilium
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-5617833	Cilium Assembly
R-HSA-5620920	Cargo trafficking to the periciliary membrane

MSigDB gene sets: 618 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_PIGMENT_GRANULE_LOCALIZATION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_VESICLE_LOCALIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT

GO Biological Process (41): heart looping (GO:0001947), protein folding (GO:0006457), spermatid development (GO:0007286), determination of left/right symmetry (GO:0007368), heart development (GO:0007507), visual perception (GO:0007601), sensory perception of smell (GO:0007608), gonad development (GO:0008406), negative regulation of gene expression (GO:0010629), artery smooth muscle contraction (GO:0014824), striatum development (GO:0021756), hippocampus development (GO:0021766), cerebral cortex development (GO:0021987), negative regulation of actin filament polymerization (GO:0030837), melanosome transport (GO:0032402), developmental process (GO:0032502), social behavior (GO:0035176), negative regulation of appetite by leptin-mediated signaling pathway (GO:0038108), positive regulation of multicellular organism growth (GO:0040018), vasodilation (GO:0042311), fat cell differentiation (GO:0045444), photoreceptor cell maintenance (GO:0045494), negative regulation of blood pressure (GO:0045776), brain morphogenesis (GO:0048854), detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), chaperone-mediated protein complex assembly (GO:0051131), cartilage development (GO:0051216), regulation of stress fiber assembly (GO:0051492), pigment granule aggregation in cell center (GO:0051877), convergent extension involved in gastrulation (GO:0060027), cilium assembly (GO:0060271), regulation of cilium beat frequency involved in ciliary motility (GO:0060296), face development (GO:0060324), response to inositol (GO:1902140), non-motile cilium assembly (GO:1905515), developmental process involved in reproduction (GO:0003006), gene expression (GO:0010467), leptin-mediated signaling pathway (GO:0033210), response to leptin (GO:0044321), animal organ development (GO:0048513)

GO Molecular Function (5): ATP binding (GO:0005524), obsolete unfolded protein binding (GO:0051082), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), motile cilium (GO:0031514), ciliary basal body (GO:0036064), kinociliary basal body (GO:1902636), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cargo trafficking to the periciliary membrane	1
Organelle biogenesis and maintenance	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
animal organ development	2
pallium development	2
cellular anatomical structure	2
microtubule organizing center	2
cilium	2
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
cellular process	1
protein maturation	1
germ cell development	1
spermatid differentiation	1
determination of bilateral symmetry	1
left/right pattern formation	1
circulatory system development	1
sensory perception of light stimulus	1
sensory perception of chemical stimulus	1
development of primary sexual characteristics	1
reproductive structure development	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
tonic smooth muscle contraction	1
vascular associated smooth muscle contraction	1
subpallium development	1
limbic system development	1
actin filament polymerization	1
regulation of actin filament polymerization	1
negative regulation of protein polymerization	1
negative regulation of cytoskeleton organization	1
negative regulation of supramolecular fiber organization	1
melanosome localization	1
establishment of melanosome localization	1
pigment granule transport	1
biological_process	1
behavior	1
biological process involved in intraspecies interaction between organisms	1
negative regulation of appetite	1
leptin-mediated signaling pathway	1
multicellular organism growth	1

Protein interactions and networks

STRING

2675 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MKKS	CCDC28B	Q9BUN5	487
MKKS	CEP19	Q96LK0	445
MKKS	B0YIZ1	B0YIZ1	444
MKKS	CFAP418	Q96NL8	419
MKKS	HSPA14	Q0VDF9	405
MKKS	BBS1	Q8NFJ9	388
MKKS	BBS5	Q8N3I7	356
MKKS	ALDH18A1	P54886	348
MKKS	CCT2	P78371	331
MKKS	TMEM67	Q5HYA8	324
MKKS	BBS10	Q8TAM1	314
MKKS	BBS12	Q6ZW61	303
MKKS	CCT5	P48643	298
MKKS	BBS2	Q9BXC9	293
MKKS	YARS1	P54577	286

IntAct

34 interactions, top by confidence:

A	B	Type	Score
BBS12	MKKS	psi-mi:“MI:0915”(physical association)	0.830
MKKS	BBS12	psi-mi:“MI:0915”(physical association)	0.830
MKKS	BBS12	psi-mi:“MI:0914”(association)	0.830
BBS12	BBS7	psi-mi:“MI:0914”(association)	0.780
BBS7	BBS12	psi-mi:“MI:0915”(physical association)	0.780
MKKS	BBS7	psi-mi:“MI:0914”(association)	0.660
BBS12	BBS10	psi-mi:“MI:0914”(association)	0.580
BBS2	MKKS	psi-mi:“MI:0915”(physical association)	0.560
CDR2	MKKS	psi-mi:“MI:0915”(physical association)	0.560
ZBED1	MKKS	psi-mi:“MI:0915”(physical association)	0.560
MKKS	TCP1	psi-mi:“MI:0914”(association)	0.530
EEF1G	INPPL1	psi-mi:“MI:0914”(association)	0.530
BBS7	TCP1	psi-mi:“MI:0914”(association)	0.460
CCDC28B	MKKS	psi-mi:“MI:0915”(physical association)	0.400
BBS10	TCP1	psi-mi:“MI:0915”(physical association)	0.400
MKKS	ZBED1	psi-mi:“MI:0915”(physical association)	0.000
MKKS	CDR2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), PTN (Two-hybrid), CDR2 (Two-hybrid), ZBED1 (Two-hybrid), MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), MKKS (Affinity Capture-MS), HSPA4 (Affinity Capture-Western)

ESM2 similar proteins: A2RT67, A2RUS2, A4IHY1, B0CM32, B0KW86, E1B8U2, E7F240, F1MDL2, O08983, O94955, O95456, P48553, Q05AX3, Q0P5F2, Q1JQA1, Q1RMZ1, Q2HJ90, Q3T0J1, Q3TLI0, Q3ZBK8, Q4KM95, Q5FVM6, Q5R4T7, Q5R989, Q5RAQ5, Q5RFG8, Q60GF7, Q6DG91, Q6VNB8, Q7Z7H3, Q80TA6, Q8BXK4, Q8CHQ0, Q8IZQ1, Q8K2I9, Q8NFZ0, Q91W96, Q92902, Q96QE5, Q99LV7

Diamond homologs: Q5R4T7, Q9JI70, Q9NPJ1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

668 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	53
Likely pathogenic	40
Uncertain significance	262
Likely benign	224
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1179069	NM_170784.3(MKKS):c.986-1G>A	Pathogenic
1379642	NM_170784.3(MKKS):c.889dup (p.Ile297fs)	Pathogenic
1408352	NM_170784.3(MKKS):c.676C>T (p.Gln226Ter)	Pathogenic
1408644	NM_170784.3(MKKS):c.375_381dup (p.Ile128fs)	Pathogenic
1433005	NM_170784.3(MKKS):c.763dup (p.Thr255fs)	Pathogenic
1439776	NM_170784.3(MKKS):c.1291_1337del (p.Ser431fs)	Pathogenic
1450424	NM_170784.3(MKKS):c.1013C>A (p.Ser338Ter)	Pathogenic
1455389	NM_170784.3(MKKS):c.175_176del (p.Gln59fs)	Pathogenic
1455421	NM_170784.3(MKKS):c.97del (p.Ile32_Val33insTer)	Pathogenic
1457348	NM_170784.3(MKKS):c.1181del (p.Leu394fs)	Pathogenic
2031791	NM_170784.3(MKKS):c.221del (p.Ile73_Leu74insTer)	Pathogenic
2119610	NM_170784.3(MKKS):c.1149G>A (p.Trp383Ter)	Pathogenic
2154926	NM_170784.3(MKKS):c.1272+2T>C	Pathogenic
21670	NM_170784.3(MKKS):c.431_441del (p.Phe144fs)	Pathogenic
21672	NM_170784.3(MKKS):c.873_876dup (p.Cys293fs)	Pathogenic
2415952	NM_170784.3(MKKS):c.1118del (p.Leu373fs)	Pathogenic
2691703	NM_170784.3(MKKS):c.885dup (p.Val296fs)	Pathogenic
2922066	NM_170784.3(MKKS):c.36dup (p.Lys13Ter)	Pathogenic
2922145	NM_170784.3(MKKS):c.1351dup (p.Cys451fs)	Pathogenic
2924131	NM_170784.3(MKKS):c.2T>A (p.Met1Lys)	Pathogenic
2927076	NM_170784.3(MKKS):c.456_459del (p.Cys152fs)	Pathogenic
2945509	NM_170784.3(MKKS):c.1190del (p.Leu397fs)	Pathogenic
2954280	NM_170784.3(MKKS):c.372_373insGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAATAAACATCTTTTG (p.Ser125delinsAlaGlyArgGlyGlySerArgLeuTer)	Pathogenic
3241927	NM_170784.3(MKKS):c.1192C>T (p.Gln398Ter)	Pathogenic
3248264	NC_000020.10:g.(?10385895)(10394162_?)del	Pathogenic
3749720	NM_170784.3(MKKS):c.13G>T (p.Glu5Ter)	Pathogenic
3754817	NM_170784.3(MKKS):c.1196T>G (p.Leu399Ter)	Pathogenic
3755605	NM_170784.3(MKKS):c.134del (p.Gln45fs)	Pathogenic
3764599	NM_170784.3(MKKS):c.599_603del (p.Leu200fs)	Pathogenic
419200	NM_170784.3(MKKS):c.1070_1071delinsAA (p.Ser357Ter)	Pathogenic

SpliceAI

1103 predictions. Top by Δscore:

Variant	Effect	Δscore
20:10407612:ATAC:A	donor_loss	1.0000
20:10407613:TA:T	donor_loss	1.0000
20:10407614:A:C	donor_loss	1.0000
20:10407722:GTGAG:G	acceptor_gain	1.0000
20:10407723:TGAG:T	acceptor_gain	1.0000
20:10407724:GAG:G	acceptor_gain	1.0000
20:10407725:AG:A	acceptor_gain	1.0000
20:10407727:C:CC	acceptor_gain	1.0000
20:10408692:T:TC	acceptor_gain	1.0000
20:10405543:T:TA	donor_gain	0.9900
20:10407611:CATA:C	donor_gain	0.9900
20:10407614:A:AC	donor_gain	0.9900
20:10407615:C:CC	donor_gain	0.9900
20:10408624:CTAC:C	donor_loss	0.9900
20:10408625:TACCT:T	donor_loss	0.9900
20:10408626:ACCTT:A	donor_loss	0.9900
20:10408627:CCTT:C	donor_gain	0.9900
20:10408690:CAT:C	acceptor_gain	0.9900
20:10408803:CCTAT:C	acceptor_loss	0.9900
20:10408804:C:CA	acceptor_loss	0.9900
20:10408804:C:CC	acceptor_gain	0.9900
20:10408805:T:A	acceptor_loss	0.9900
20:10408811:T:TC	acceptor_gain	0.9900
20:10420523:CTTA:C	donor_loss	0.9900
20:10420524:TTA:T	donor_loss	0.9900
20:10420525:TACC:T	donor_loss	0.9900
20:10420526:A:AT	donor_loss	0.9900
20:10420527:C:CG	donor_loss	0.9900
20:10420757:ACC:A	acceptor_loss	0.9900
20:10420760:T:G	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000046948 (20:10401146 C>T), RS1000074626 (20:10412647 G>C), RS1000098113 (20:10408560 A>G), RS1000264257 (20:10418981 CT>C), RS1000384323 (20:10406224 A>C), RS1000400778 (20:10432564 G>A), RS1000521130 (20:10423969 CAT>C), RS1000782947 (20:10406912 A>G), RS1000841283 (20:10434565 C>T), RS1000992402 (20:10417521 G>A), RS1001108012 (20:10407142 G>C), RS1001211555 (20:10414221 G>A,C), RS1001214498 (20:10421472 G>A), RS1001329854 (20:10407871 T>A,C,G), RS1001401637 (20:10424885 C>G)

Disease associations

OMIM: gene MIM:604896 | disease phenotypes: MIM:236700, MIM:605231, MIM:209900, MIM:173900, MIM:256100

GenCC curated gene-disease

Disease	Classification	Inheritance
McKusick-Kaufman syndrome	Definitive	Autosomal recessive
Bardet-Biedl syndrome 6	Strong	Autosomal recessive
ciliopathy	Strong	Autosomal recessive
Bardet-Biedl syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
MKKS-related ciliopathy	Definitive	AR

Mondo (9): McKusick-Kaufman syndrome (MONDO:0009367), Bardet-Biedl syndrome 6 (MONDO:0011523), Bardet-Biedl syndrome (MONDO:0015229), inherited retinal dystrophy (MONDO:0019118), multicystic dysplastic kidney (MONDO:0015988), polycystic kidney disease (MONDO:0020642), nephronophthisis (MONDO:0019005), MKKS-related ciliopathy (MONDO:1040050), ciliopathy (MONDO:0005308)

Orphanet (5): Bardet-Biedl syndrome (Orphanet:110), McKusick-Kaufman syndrome (Orphanet:2473), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Multicystic dysplastic kidney (Orphanet:1851), Nephronophthisis (Orphanet:655)

HPO phenotypes

134 total (30 of 134 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000072	Hydroureter
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000100	Nephrotic syndrome
HP:0000107	Renal cyst
HP:0000113	Polycystic kidney dysplasia
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000143	Rectovaginal fistula
HP:0000145	Transverse vaginal septum
HP:0000147	Polycystic ovaries
HP:0000148	Vaginal atresia
HP:0000163	Abnormal oral cavity morphology
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000388	Otitis media
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000470	Short neck

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D021782	Multicystic Dysplastic Kidney	C12.050.351.875.558; C12.050.351.968.419.403.750; C12.200.706.629; C12.200.777.419.403.750; C12.800.629; C12.950.419.403.750; C16.131.939.629
D007690	Polycystic Kidney Diseases	C12.050.351.968.419.403.875; C12.200.777.419.403.875; C12.950.419.403.875; C16.131.077.717; C16.320.184.625
D058499	Retinal Dystrophies	C11.768.585.658
C565738	Bardet-Biedl Syndrome 6 (supp.)
C538159	McKusick Kaufman syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Asbestos, Crocidolite	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
dicrotophos	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
nickel sulfate	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
bisphenol S	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Gasoline	increases abundance, affects cotreatment, decreases expression	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Zinc	affects cotreatment, increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

88 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03746522	PHASE3	COMPLETED	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
NCT04966741	PHASE3	COMPLETED	Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03490019	PHASE2	WITHDRAWN	Treatment of Bardet-Biedl-Syndrome With Metformin for Evaluation of a Possible Visual Improvement
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT02140814	PHASE2	COMPLETED	Uncontrolled, Open Label, Pilot and Feasibility Study of Niacinamide in Polycystic Kidney Disease
NCT02558595	PHASE2	COMPLETED	Pilot Study of Niacinamide in Polycystic Kidney Disease (NIAC-PKD2)
NCT02697617	PHASE2	COMPLETED	Use of Low Dose Pioglitazone to Treat Autosomal Dominant Polycystic Kidney Disease
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT03101891	PHASE1	ACTIVE_NOT_RECRUITING	Renal Anhydramnios Fetal Therapy
NCT02166489	PHASE1	COMPLETED	Mesenchymal Stem Cells Transplantation in Patients With Chronic Renal Failure Due to Polycystic Kidney Disease
NCT00078091	Not specified	TERMINATED	Genetics and Clinical Characteristics of Bardet-Biedl Syndrome
NCT00213811	Not specified	COMPLETED	Bardet-Biedl Syndrome Study: Clinical and Genetic Epidemiology Study in Adults
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT02329210	Not specified	RECRUITING	Clinical Registry Investigating Bardet-Biedl Syndrome
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT04461444	Not specified	RECRUITING	COhort for Bardet-Bield Syndrome and Alström Syndrome for Translational Research Monocentric Interventional Study
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT05183802	Not specified	APPROVED_FOR_MARKETING	An Expanded Access Protocol for Setmelanotide for Treatment of Bardet-Biedl Syndrome (BBS)
NCT05400278	Not specified	COMPLETED	Characterizing the Genotype and Phenotype in Adults With Bardet-Biedl Syndrome
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT06615011	Not specified	NOT_YET_RECRUITING	Bardet Beidle Syndrome in a Syrian Adolescent : a Rare Case Report
NCT07602803	Not specified	COMPLETED	The Effect of GLP1 Agonists on Weight Loss in BBS Cohort in the UK
NCT00068224	Not specified	COMPLETED	Clinical and Molecular Investigations Into Ciliopathies
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases